Nuclear PARPs and genome integrity

Abstract

Effective maintenance and stability of our genomes is essential for normal cell division, tissue homeostasis, and cellular and organismal fitness. The processes of chromosome replication and segregation require continual surveillance to insure fidelity. Accurate and efficient repair of DNA damage preserves genome integrity, which if lost can lead to multiple diseases, including cancer. Poly(ADP-ribose) a dynamic and reversible posttranslational modification and the enzymes that catalyze it (PARP1, PARP2, tankyrase 1, and tankyrase 2) function to maintain genome stability through diverse mechanisms. Here we review the role of these enzymes and the modification in genome repair, replication, and resolution in human cells.

Keywords: PARP; genome integrity; tankyrase.

Figure 1.

Primary structure and mode of action for PARP1 and PARP2 and tankyrase 1 and tankyrase 2. (A) Schematic representation of PARP1 and PARP2. (Zinc fingers) Zn1, Zn2, and Zn3; (BRCT) BRCA C terminus; (WGR) Trp–Gly–Arg domain; (HD) helical domain; (ARDT) ADP-ribosyltransferase. (B) PARP1 or PARP2 is regulated through its catalytic activity. Inactive PARP1 binds to breaks and is activated to undergo autoPARylation. PAR serves to recruit DNA repair proteins. (C) Schematic representation of tankyrase 1 and tankyrase 2. (HPS) His–Pro–Ser domain; (SAM) sterile α module; (ART) ADP-ribosyltransferase. (D) Tankyrase 1 or tankyrase 2 is regulated through its selection of binding partners. Constitutively active tankyrase binds to RxxxxG-containing proteins and localizes throughout the cell for multiple functions. Tankyrase may (or may not) PARylate its partner.

Figure 2.

List of validated tankyrase-binding partners and their localizations throughout the cell. (A) A chronological list of human tankyrase-binding partners that have been validated by protein coimmunoprecipitation. For each protein, the list includes its subcellular location(s), its “RxxxxG” consensus tankyrase-binding site (“——” if not found in the amino acid sequence), and a reference for the publication identifying the interaction. Protein location(s) were curated through a literature search and the UniProt protein database. (N.D.) Not determined. (^a) The protein contains additional binding motifs in its sequence. (^b) The binding site is noncanonical. (^c) The binding site is conserved among protein family members. (B) Schematic representation of the localization of tankyrase binding proteins (listed in A) to the indicated organelle(s). Circle size is based on the number of tankyrase-binding proteins localized to the organelle(s). The overlap between an organelle(s) circle with the “nucleus” circle represents the number proteins found in both.

Figure 3.

Tankyrase is required for resolution of telomeres and rDNA. (Top panel) In control cells, arm and telomere cohesion is released in G2/prophase, followed by resolution of centromere and rDNA at the metaphase to anaphase transition. (Bottom panel) In the absence of tankyrase 1, arm cohesion is released in G2/prophase, followed by release of centromere cohesion at the metaphase to anaphase transition. Resolution of telomeres and rDNA is delayed until anaphase leading to anaphase delay, rDNA damage, and aneuploidy.